Indenopyran- and indenothiopyranalkylamines

ABSTRACT

Indenopyran- and indenothiopyranalkylamine derivatives characterized by having an amino(lower)alkyl radical attached to the 1 position of an indeno(2,1-c)pyran or indeno(2,1-c)thiopyran nucleus are disclosed. Also included are the corresponding derivatives having an indeno(1,2-c)pyran and an indend(1,2-c)thiopyran nucleus. The amino portion of the amino(lower)alkyl radical may be further substituted with one or two lower alkyl groups or incorporated into a heterocyclic amine radical. The derivatives are further substituted at position 1 and may be optionally substituted at positions 3, 4, 5, 6, 7, 8, and 9. The indenopyran- and indenothiopyranalkylamine derivatives of this invention are useful antidepressant agents. Methods for their preparation and use are disclosed.

United States Patent [1 1 Jirkovsky et al.

[ 1 *Oct. 7, 1975 1 INDENOPYRAN- AND INDENOTHXOPYRANALKYLAMINES [75]inventors: lvo Jirkovslty: Leslie G. iiumber;

Christopher A. Demerson; Thomas A. Dobson, all of Montreal. Canada [73]Assignee: Ayerst, McKenna and Harrison Ltd., Montreal. Canada 1 Notice:The portion of the term of this patent subsequent to Dec. ll, i990, hasbeen disclaimed.

[22] Filed: July 9, 1973 [21] Appl. No.: 377,696

Related US. Application Data [631 Continuation-impart oi Ser. No.291,129. on. l2,

i972, Pat. No. 3,778,449.

[52] US. Cl. 260/327 TH;260/2471P; 260/2472 B; 260/247.7 A; 260/247.7 E;

260/268 TR; 260/293.57. 260/293.58i

[5 l] int. Cl. C07D 335/04 [58] Field of Search 260/327 TH, 345.2,326.34. 260/3265 SA, 326.5 CA, 326.84, 293.57,

293.58, 247.l P, 247.2 B, 247.7 A. 268 TR,

[56] References Cited UNITED STATES PATENTS 3,778,449 l2/l973 Jirkovskyet al. 260/327 TH FOREIGN PATENTS OR APPLICATIONS 2,05l,496 4/l97lGermany OTHER PUBLICATIONS Warren. Synthetic Methods of Org. Chem., Vol.13, No. 749 (i959).

Rieche, Synth. Meth. of Org. Chem., Vol. 12. No. 824 (i958).

Fieser, Reagents for Org. Syn. (1967), pp. 6l5-6l7. Zalicky, Chem. ofAmides (1970), pp. 96-l05. Pfitzner, J.A.C.S. No. 87:5670+( I965).

Campbell. J.A.C.S. No. 70:38684-(1948).

Leonard. .I.O.C. No. 28:19374-(1968).

. Schenker, Angew. Chem. 73:8l( 196i).

Delepine, Compt. rend. l49:39( 1909).

Morrison, Org. Chem. (1959) pp. 339. 344, 345, 486, 633.634.

Fieser ll, Adv. Org. Chem. (i961) pp. 495, 496, 505.

Roberts, Basic Principles of Org. Chem. (1964), pp. 658-660.

Primary Examiner-Henry IR. .liles Assistant Examiner-C. M. S. aisleAnorney.Agen. or Firm-John P. Floyd 5 7 ABSTRACT optionally substitutedat position's 3, 4, 5, 6, 7, 8, and

9. The indenopyranand indenothiopyranalkylamine derivatives of thisinvention are useful antidepressant agents. Methods for theirpreparation and use are disclosed. v,

48 Claims, No Drawings INDENOPYRAN- AND INDENO'I'HIOPYRANALKYLAMINI'BThis application is a continuation-in-part of Ser. No. 297129. filedOct. l2. 3778449, issued Dec. l 1. I973.

BACKGROUND OF "ma INVENTION l. Field of the Invention I972. now US. Pat.No. 5

. DETAILED DESCRIPTION OF THE INVENTION The term lower alkyl as usedherein contemplates straight chain alkyl radicals containing from one tosix carbon atoms and branched chain alkyl radicals con- This inventionrelates to novel indenopyran and i mi i th t f carbon d includgg h Lindenothiopyranalkylamine derivatives. to processes for theirpreparation and to intermediates used in these processes.

More specifically. the present invention relates to novel indenopyranandindenothiopyranalkylamine l derivatives possessing valuablepharmacologic proper ties. For example. these derivatives exhibit usefulantidepressant properties atdosages which do not elicit undesirable sideeflects. The combination of this property together with a low order oftoxicity render the lndenotion therapeutically useful.

2. Description of the Prior Art Prior interest in the field ofindenopyrans and indenothiopyrans has been so limited thatitmay beconsidered practically' non-existant. Apparently. the closest prior artto the compounds of the present invention would be a few unrelatedreports dealingwith chemical aspects of certain compounds withindenopyran ring systems. For example. in a report by'N. Campbell. etal., J. Chem. Soc., 993 i963). the authors postulate that certainneutral .I indenol2.l-c]- or; indeno[ l.2-c]pyran derivatives may beproduced by the reaction of Z-benzylideneindan-l-one and diphenylketone.

I SUMMARY OF THE INVENTION 1 The indenopyranandindenothiopyranalkyla'mine derivatives of this inventionarecharacterizedby having an amino(lower)alkyl radical attached to' 'a indenopyran orindenothiopyran nucleus. The preferred derivpyranandindenothiopyranalkylsmines of the invenatives of this invention arerepresented by formulae I or ethyl propyl. isopropyl, butyl. isobutyl.pentyl and the like.

The term lower alkoxy as used herein contemplates both straight andbranched chain alkoxy radicals containing from one to four carbon atomsand includes methoxy. ethoxy. isopropoxy and the like.

The term "lower alkanoyloxy as used herein contemplates both straightand branched chain alkanoyloxy radicals containing from two to sixcarbon atoms and includes acetoxy. propionyloxy, hexanoyloxy and thelike.

The term "halo" as used herein contemplates halogens and includesfluorine. chlorine. bromine and lodine. I

The indenopyranand indenothiopyranalk'ylamines of formulae I and la' arecapable of forming-acid addition salts with pharmaceutically acceptableacids. Such acid addition salts are includedwithin the scope of thisinvention.

The acid addition salts are prepared by reacting the base form of theappropriate indenopyran and indenothiopyranalkylamines withsubstantially one or two equivalents. depending on the number of basicnitro- 5 gens in the compound. or preferably with an excess of theappropriate acid in an organic solvent. for example.

ether or an ethanol-ether mixture. ,These salts. when administered tomammals. possess the same pharmaco- Iogic activities as thecorresponding bases-For vmany 40 purposes it is preferable toadministerthe salts rather than the base compounds. Among the acid addition saltssuitable for-this purpose are salts such as the sulin which R is loweralkyl; RKR'. R and R are the same or different selected from the groupconsisting of I hydrogen and lower alkyl; R' is hydrogen, lower alkyI.hydroxy, lower alkoxy. lower alkanoyloxyor haloy R' is hydrogen or loweralkyl', X is oxy or thio; and Y is an amino (lower)alkyl radical offormula Allt NR'R' where Alk is an alkylene selected fromthe groupconsisting of V CR'R". CRIR CIU'R". CR'R"CR"R"CR!R" andCR'R"CR"R"CR"R"CRI'R". wherein R". R, R". R". R". R". R" and R? arehydrogen or lower alkyl and R' and R' are either the same ordifferentselected from the grou'pccnsisting of hydrogen and loweralkyl.

"or R and R' together with the nitrogen atclm'towhicli;

they are joined form a heterocyclic amine radical se- I fate. phosphate.lactate, tartrate. maleate. citrate, hy-

' jdrobromide and'hydrochloride. Both the base compounds and the saltshave the distinct advantage of possessing a relatively lower order oftoxicity.

' Also included in this invention are the stereochem- Ical isomersof thecompounds of formulae l and la which result from asymmetric centers.contained therein. These isomeric forms may be prepared by chemicalmethods and are purilled readily by crystallination or chromatography.

p, Individual optical isomers. which might be separated by fractionalcrystallization of the diastereoisomeric salts formed thereof. forinstance, with dor l-tartaric acid orD (+)-ol-bromocamphor sulfonicacid. are also included.

ranand indenothiopyranalkylamines of formulae l and la and their acidaddition salts with pharmaceutically acceptable acids may bedemonstrated in standard pharmacologic tests. such as.for example. thetests demented that reserpine in animals produces a model dels prcssionwhich can he used for detecting antideprcs sant properties. Accordingly.the compounds of the present invention antagonize reserpine effects inmice at doses ranging from about lto 100 mg/kg. Several of the preferredcompounds, for instance.

N.N. l -trimethyl-l .3.4.9-tetrahydroindeno[ 2. l -c lpydemonstrated inthe test of DE. Bogdanski et al.. 'J.

Pharmac. Exp. Ther.. I22. 182 (i958). is a desirable feature foratherapeutic agent used to alleviatethc symptoms of depression especiallywhenit isdesired primarily to elevate the mood of thepatienta When theindenopyranand indenothiopyranalkyla mines of this invention are used torelieve the symptoms of depression in warm-blooded mammals. e.g. ratsand mice. they may be used alone or in combination withpharmacologically acceptable carricrs..the proportion of which isdetermined by the solubility and chemical nature of the compound. chosenroute of administration and standard biological practice. For example.they may be administered orally in solid form containing such excipientsas starchrmilk sugar.,ce'rtain types of clay and so forth. They may alsobeadminisformula ll,

tered orally in the form of solutions or they may be injectedparenterally. For parenteral administration they may be used in the formof a sterile solution Containing other solutes. for example. enoughsaline or glucose to 5 make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore. it willvary with the particular host under treatment. Generally. treatment isinitiated with small dosages substantially less than the optimum dose ofthe compound. Thereafter. the dosage is increased by small incrementsuntil the optimum effect under the circumstance is reached. In general.the compounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects and preferably at alevel that is in a range of from about ().i mg to about mg per kilo 20per day. although as aforementioned variations will occur. However. adosage level that is in the range of from about 0.5 mg to about 25 mgper kilo per day is most desirably employed in order to achieveeffective results.

Processes For the preparation of the lndenopyranandindenothiopyranalkylamine derivatives of formula I we prefer touse asstarting materials the compounds of general in which R. R". R. R". R andR are as defined in the first instance and X is hydroxy. mercapto.-S-,SO Na or --S.SO;,K.. The starting material of formula II.indcne-3-ethanol (ll. X OH and R. R". R. R. R and R H). is well knownand its synthesis by a variety of methods has been reported; forexample. see G-R. Clemo. et al.. J. Chem. Soc.. 863 (i and F.H. Howelland D.A.H. Taylor. J. Chem. Soc.. 30ll (1957). For the preparation ofthis starting material as well as the other requi- .site startingmaterials of formula "in which'X is bydroxy the following two generalprocesses are convenient. .The firstprocess may be illustrated asfollows:

With reference to this first process the cyclization of the appropriatephenylpropionie acid derivative. see

Chemistry of Carbon Compounds. Vol. III A. E. H. Rodd. Ed.. ElsevierPublishing Co.. Amsterdam. i954.

pp. 593-598. is accomplished by treatment with an i972 to give the endoester V or a mixture thereof with the exo'ester Vi in the case where Rof the Reformatski reagent is hydrogen. The ester V or the mixture ofthe latter esters are then reduced by lithium aluminum hydride and thedesired compound of formula ll ()0 I OH and R and R" H) separated fromthe reaction product by conventional means such as chromatography orrecrystallization. I The second process may be illustratedas follows:

VIII.

VII.

With reference to this second process the approprif ate indenederivative of formula Vll. see .Chemistry of the Carbon Compounds. Vol.ill B. cited above. i956.

pp. l256-l26l. A. Panetta'and C. Bunce'. J.-Org Chem. 4859 (196i) andM.L. Tamayo and N. D. Ro-

bles. Anales Real Soc. Espan. Fis. Y.Ouim.. 528. I I7 (i956). [CherniAbst., 50. 14676 l956)]. is converted to its corresponding lithiumderivative by treatment with butyl lithium in tetrahydrofur an. fl,hecorrespond} ing lithium derivativeis thenjtreated with ethylene, g.

oxide or a lower alkyl substituted ethulene oxideijto afford the desiredstarting material of formula ii in which I X is hydroxy. The desiredstarting materials may also be obtained by treating the appropriateindenederiva-i tive of formula Vii with the appropriate ethyieneloxldederivative according to the procedure of M. .luliaget ai.. Bull. Soc.Chim. Fr.. 229K 1966). for reacting eth-,."

ylene oxide with indoie..

The lower alkyl substituted ethylene] oxides are pre pared by knownmethods: for example". see .V.. Franzen and H. E.Driesen. Chem. Ber.." 96 88l (l 9 6 3). r The starting materialsof formula lllin which. X. isfmercapto. SSO,.' Na' or SSO,-,K and R". Ri'. q

R. R". R and R are as defined in the first instance may be obtained bythe following processg 'lhe.appropriate, compound of formula i l(Xl;fiOl-i){described abovepi is treated-with phosphorustribromide in aninertsoli vent. for example. ether or carbon tetrachloride. to af-' Yford the corresponding 3.-( 2-bromoethyl )-indene derivative. in thecase where X'ishydroxy and RKR". R.

R". R" and R? are hydrogen.,.the ,corresponding 3-(2-bromoethyl)indenederivative obtained is 3-(2- indoie-Ii-ethanethiol.

Accordingly. the appropriate 3-(2-bromoethyi)indene derivativeis treatedwith sodium or potassium thiosulfate to afford the corresponding sodiumor potassium fl-(li-lndenyliethyl thlosuifate derivative. rclpeetlveiy.namely. the desired starting material oi rarmuia ll (X SSO,.Na orS-SO..-K). Treatment of the latter derivative with strong alkali. forexample. sodium or potassium hydroxide. yields the correspondingbis-[o-( ii-indenyl )etll1yl]disulfide derivative. Reduction of thelatter compound with lithium aluminum hydride gives the desired compoundof formula ii in which X is mercapto.

On the other hand the preceding thiosulfate derivative is treated withacid. for example. dilute aqueous solutions of hydrochloric acid.sulfuric acid or phosphoric acid. to' give directly the compound offormula llinwhich X is mercapto.

it should be noted that the preceding process may not beentirelypractical for the preparation of the compound of a formula ii in which Xis mercapto. S-SO -,Na or SO,-.K and R" is hydroxy or lowerall-tunoyloxy. For this reason. the preferred start-. ing materials offormula ii for the ultimate preparation of the compounds of formula I inwhich R" is hydroxy or lower alkanoyloxy and X is thio. S-SO.,Na or'S-SO.,K are the corresponding compounds of formanner. they are firstsubjected to the processtll l X -X).described below. Subsequently. thebenzyloxy group is removed by-hydnogenation. in'the presence of acatalyst.- for example.l0% palladium on carbon. just prior to affordingthe desired corresponding compound of formula I in'which R is hydroxy.The latter may be converted if desiredto the corresponding compound offormula I in which R is lower alitunoyloxy by conventional means. forexample. by treatment with the appropriate lower alkanoie anhydridepreferably in the presence of pyridine.

Likewise. it should be notedthat similar use of the startingmaterials;of formula ii in which Xis hydroxy and R" lsbenzyloxy toobtainthe corresponding compound offormula'l in which R is hydroxy or loweralkanoyloxy; is also preferred.

The above describedstarting material of formula il l in whtnja Ma ea". Rand x' are defined in the first-instance is utilized for the preparationof the corresponding compbund of formula I by subjecting it to-a i t'eyreaction comprising the treatment said starting matcriaiwithsubstantiallyan equivalent amount of a compound of formula tiXi which Ris as defined in the first instance and Y is selected from the groupconsisting of:

a. COOR and Ali-t COOR in which R" is hydroc. CH- OCOR andAlk-CH-.OCOR"' in which R is.

hydrogen or lower alkyl and AIR hereinbefore.

d. Alk-L in which Alk is an alkylene selected from the group consistingof CRRCHR. CR"RCR'*RCHR and CRR"CR"RCRR"CHR' wherein R". R. R". R". R.R. and R are as defined hereinbefore and L is halo.

c. Aik NR*COR in which Alk and R" are as defined herein and R" ishydrogen or lower alkyl containing from one to five carbon atoms.

f. Alia-NO, in which Alk is us defined hereinbefore.

and

g. Alk-NR"R" in which Alk. R" and R are we defined hereinbefore. in thepresence of an acid catalyst to yield the compound of formula X in whichR. R". R. R. R. R". R. X and Y are as defined hereinbefore.

Accordingly, when Y is the group Alk-NRR'. the compound of fonnula l isobtained directly, and when is as defined trifluoride. zinc chloride.hydrochloric acid. perchioric acid. trifiuoroacetic acid. sulfuric acid.and polyphosphoric acid and the like. Boron trifluoride.p-toiuenesuifonic acid. aluminum chloride. and trifiuoroacetic acid areincluded among the preferred acid catalysts. The amount of acid catalystused is not especially critical and may range from 0.0i molarequivalents to 100 molar equivalents with respect to the startingmaterial of formula ii. A range of from 0.1 to l0 molar equivalents isgenerally preferred; however. note that the amount of acid catalystshould be in excess of one Y is other than Alit-NR'R'. as noted above.the novel compounds of formula I are prepared by transformation of saidcompounds of formula X by standard methods. several of the moreconvenient and practical math ods being described in detail hereinafter.

when practising the condensation (ll-ilX e. X) a a solvent is generallyused as a reaction medium. Anysolvent inert to the reaction conditionsmay be used. Suitable solvents include benzene,'toluene. diethyl ether.dioxan. tetrahydrofuran. methylene chioride. carb on tetrachloride andthe like. Benzene and tetrahydro llllllli are heated to a melt withstirring.

A variety of suitable acid catalysts may be used for molar equivalentwith respect to the compound of formula O Rel-Y when Y is Alk-NRR".

The time of the reaction may range from l0 minutes to hours. with thepreferred range being from onehalf to 24 hd'urs. The temperature of thereaction may range from 20C to l60C.

A more detailed description of the preparation of the above compounds offormula X and a description of their subsequent conversion toindenopyranandindenotiiiopyranalkylamine derivatives of formula 1 aredisclosed below. For convenience these descriptions are catagorized intosections according to the group selected for Y for the intermediate.

; 'a. Preparation and Conversion of Intermediates of Formula X (Y' ICOQR and Alk-COOR') Intermediates of formula X (Y COOR and Mk- OOOR"wherein R is hydrogen or lower alkyl and Aik is as defined in the firstinstance) are readily obtained by the condensation (ll [X X) by usingketoaeids or ketoesters of formula in which R is as defined in the firstinstance and Y is COOR" or Alli COOR" as diefined above together withthe starting material of formula ll.

Generally comparable yields of product are obtained in this process wheneither the itetoacid or the corresponding ketoester is used. However. inthe case where it is desired to prepare an acid compound of formula X inwhich Y is AlkCOORi wherein Alk is CRR" and'R is hydrogen (i.e.. anacidintermediate of formula X). it is preferable to first condense theappropriatefi-ketoester of formula IX rather than the correspondingB-ketoaeid and then hydrolyze the resulting ester product to give thedesired acid compound.

Moreover. in the general practise of this invention it is ottemmoreconvenient to prepare the acid compounds of formula X by using theketoester instead of the ketoacid in this processand hydrolyze theresulting ester product to the desired acid. the reason being simthiscondensation. for example. the type of catalyst used in a Friedel-Crafisreaction. i.e.. p-toluenesulfonic acid. aluminum chloride. phosphoruspentoxide. boron ply that the ketoesters are generally more readilyavailable either commercially or by synthesis.

The hydrolysis of compounds of formula X in which Y is COOR'" 0rAiitCOOR" wherein Alk" is as defined in the first inst'ance and R"islower aikyl. i.e.

' ester intermediatcitof formuiaX.to their corresponding acids offormula X. is readily effected by treatment with a suitable alkali. forexample. potassium hydroxide or sodium carbonate. in aqueous methanol oraqueous ethanol or by treatment with lithium iodide in a suitableorganic solvent. forexample. collidine.-see L. F. Fieser and M.FieserCReagents for Organic'Synthesis". John Wiley and Sons. lnc..New'York. i967. pp'.-6lS-6l7.

The oz-. 13-. 'yand S-ketoacids and -ketoesters of formula lX are eitherknown. for example. ethyl pyruvate. ievulinic acid. ethyla.a-dimethylacetoacetate. and

Bfi-dimethyllevulic acid. or they may be preparedgby known methodsdescribed in general organic chemistry.

textbooks. For'examplc. a comprehensive review of the properties andpreparation of such a-.'B-. 'y-.and o-ketoacids and ketoesters may befoundin Rodds Chemistry of the Carbon Compounds. 8." Coffey. Ed.. Vol.irl. 2nd ed.-. Elsevier Publishing Co.'. Amsterdam. 1965. PP. 226-274.

Thereafter theseintermediate acids and esters of foroftriethylamine.'aifording theeorresponding mixed anhydridc. which isconverted by treatment-with the appropriate amine of formula HNR"R" inwhich R and R are as defined in the first instance. forexample. am-

monia. methyla'mine 'or dimethyiamine. to yield the corresponding amideof formula X in which Y 'is CONR'R" Ot' Alk'CONR"R in which Alk'. R andR are as described in the first instance.

Alternatively. the latter amides areaiso obtained by.

treating the ester intermediates of formula IX with the appropriateamine according to known amidation methods. for'example, seeA. L.FLBeckwith in The Chemistry of Amides J. Zaiicky. Ed.. intersciencePublishers. New York. 1970. pp. 96405.

Thereafter. the amides so obtained are reducedwith a suitable complexmetal hydride to yield the desired indenopyranandindenothiopyranalkylamines. Examples of suitable complex metalhydridesj'are lithium aiuminu'm hydride. lithium aluminumhydridealuminum chloride. aluminum hydride-aluminum chloride. diboraneand sodium borohydride-aluminum chloride. Lith ium aluminum hydride ispreferred.

Amodification relating .to'the preceding general re-g duction of theabove amides of formula X in which Y Y is CONR'R or 'AIW-CONNR whereinAlk. R" and R is as definedin the first instance is applicable to thereduction of the tertiary.- secondaryfand primary amides. describedherein. and is a preferred modification for: the reduction of the lattertwo. in practising thisrnodification. the'aforementionedamide of formulaX is treated with triethyloxonium flaorobora'te. or dimethyl sulfate.see H. Bredcreck. et ai.. Chem. Ber.. 98. 2754 (i965). in an inertsolvent. for example. methylene dichloride. whereby the correspondinglmlnoether fluoroborate ormethyl sulfate salt is obtained. respectively.

complex i metal hydride. similar to the" reduction described "previouslyfor the amides. yieldsl'fthe corresponding compounds of formula I.Alternatively; the

above fluoroborate or methyl sulfate salt derived from a secondary orprimary amide may be decomposed b base treatment. for example. with 10%sodium hydrid or tricthylamine. to give the corresponding iminoethc 5which is then reduced in a like manner to the desiret compound offormula i.

When applying the aforementioned steps in the prep aration of compoundsof formula I in which R" is by droxy or lower alkanoyloxy. it ispreferable to use cor responding intermediates in which R" is benzyioxyfol lowed by the appropriate transformations as noted prc viousiy toyield the desired compounds of formula I.

b. Preparation and Conversion of intermediates of Fonnula X (Y' CONRRand Alk'-CONR"R").

The intermediates of formula X in which Y i CONR"R" and Alk-CONR"Rwherein R". R and Alkare as defined in the first instance. described inthe pre vious section. are also obtained directly by utilizing iiiappropriate starting materials of fom'iula ii and a. B- 7-. orS-ketoamides of formula in which R is as defined above and Y is CONR"R"u Alk'-CONRR" in which Aik'. R" and R as as dci'inci above. Theketoamldes required for this condensatio:

. are either known. for example. pyruvamide oa,a-dimethylacetoacetamide. or they may be prepare by known methods. forinstance. see Rodds Chemis try of the Carbon Compounds". cited above.Vol. il. pp. 226-274.

. Thereafter these amides are converted by the reduc tion process.described above. to the compounds of for mula i in which R. R. R" R. R.R". R and X are a defined in the firstinstance and Y is -Aik-NR"R" iwhich Alk is CH, or Alk-CH=wherein Alk' is as dc fined in the firstinstance and R" and R are as define in the first instance. t

i c. Preparation and Conversion of intermediates of Formula X (Y Cl-iOCOR and Alk'-CH-,OCOR* intermediates of formula X in which Y is CH CCOR" and AIk CH CJ'COR" wherein AIR and R ar as defined in the firstinstance. are obtained when starting material of formula II is condensedwith a kc toaicoholflower aikanoic acid "ester. of formal RFCQCH QCORK'or RCO-Alk-CH,OCOR" in whic R ;Aik and R are as defined in the firstinstance i the presence of a suitable acid catalyst according to thconditions described above for the condensation (ll IX X). Theketoaicohol lower alkyl esters are eithe known. for example. 'acetonyiacetate or 5 acetoxypehtan-Z-one. or may be prepared by knowmeth'ods.'for instance. see Rodds Chemistry of th Carbon Compounds".cited above. Vol. id. pp. 49-54 These intermediates of formula X areutilized for th able alkali. for example. sodium hydroxide in aqueouSubsequent reduction of the sait'thus'obtained with a methanol to affordthe corresponding primary alcoho it should be noted fliSO that thelatter primary alcohc is obtaineddirectly by the reduction of theappropriat intermediate acids or inten'nediate estersof formula Xdescribed herein in section (11). using a suitable com plex metalhydrideas described therein. The primary alcohol is then oxidized to thecorresponding aldehyde. Although a variety of methods are known for theoxida-.

tion of a primary alcohol to its corresponding aldehyde. see forexample. Rodds Chemistry of the Carbon Compounds. cited above. Vol. lc.pp. 4- -l(l. we have found the method of K; E. Pfitzner and J. G.Moffat. J. Am. Chem. Soc.. 87. 5670 (i965). usingN.N-tlicyclohexylcarbodiimidc and dimethyl sulfoxide in the presence ofa suitable acid. for example. trifiuoroacetic acid. to be bothefficacious and convenient. 'l'herealter the aldehyde is reacted withttn amide of the formula HNlt R in which R" and R" are as defined in thefirst instance according to the method of K. N. Campbell. et al.. J.Amer. Chem. Soc.. 70 3868 i948). in the case when the amine used isammonia or a primary amine. or according to the method of N. J. Leonardand J. V. Paultstelis. J. Org. Chem.. 28. 1937 i963 when the amine is asecondary amine. to give the corresponding Schiff base or immoniumsalt.'respcctiveiy. The product so obtained is reduced with sodiumborohydride. see E. Schenker. Angew. Chem..

ing halide. inesylate or tosylate. which is then reacted with two ormore molar equivalents of an amine of formula HNRR" in which R" and R"are as defined in the first instance. Preferably this reaction isperfonnedin a suitable inert solvent. for example. tetrahydrofuran. atthe boiling point of the reaction mixture for a period of eight to 24hours. in connection with alkylations of amines of formula HNR R" inwhich R is hydrogen and R" is lower alkyl as disclosed herein. it isgenerally prefcrablc to perfonn to alkylation with the correspondingN-benzyl derivative of said amine. i.e.. an amine of for- -Ail -NR"R"wherein Alk is CH, or AllU-CH, wherein Aik' is as defined in the firstinstance and R" is hydrogen or lower'alltyl and R is lower alkyl (i.e.secondary ortc'rtiary amines with respect to Y). In this case dependingon the particular derivative desired the N- mula HNR"R in which R" isbenzyl and R is lower alkyi. Thereafter. when 'allappropriatetransformation have been performed. the N'benzyl group may beremoved by hydrogenolysis with a catalyst preferably 10% palladium oncarbon. to give the desired compounds of formula I.

Alternatively. thc'above aldehyde is oxidized with intermediatesofformala X described in'section. (a). Although a variety of suitableoxidizing agents may be pine and P. Bonnet. Compt. rcnd.. l49.39 i909).

Again alternatively. the above aldehyde is converted a suitableoxidizing agent to yield the corresponding acid alkylation may beeffected with one or two moles of the alkyl halide to give respectivelythe secondary (R" H and R lower alkyi) or tertiary amine (R" R" equalslower alkyl).0n the other hand the N-alkylation may be effected in twosteps introducing a different alkyl group each time to afford thecorresponding tertiary amine in which R" and R are different loweralkyls.

When it is desired to prepare the above tertiary amine compounds inwhich R" or R" are either or both methyl. an alternative alkylatlonmethod comprises reacting the appropriate corresponding primary orsecondary amine with an aqueous mixture of a substantial excess offormaldehyde and formic acid according to the conditions of theEschweiler-Clarke reaction. see M.- L. Moore. Organic Reactions. 5. 30l(i949). whereby N-methylation is effected.

Another N-alkylation method which may be applied to'the above primaryand secondary amines involves acylation with a lower alkanoic anhydrideor acid halide and subsequent reduction of the resulting amide.

Furthermore. the above primary amines may be used to prepare compoundsof formula I in which Y is -Alk- NR". R wherein Alk is CH, or Alk' -CH,and R and R together with the nitrogen atom to which they are joinedfrom a heterocyclic amine radical as defined in the firstinstance. Whenused in this manner the primary amines are subjected to known.N-alkylation methods. forexample. see method J described by R. B.Motfet. J. Org. Chem. i4. 862 i949) with the appropriate a.-.dibromides.for example. tetramethylene dibromide. 'pentamethylene dibromide. bis(2-chloroethyl )cthcr. bis( 2-chloroethyl )bcnzylamine followed byhydrogenation in the presence of 10% palladium on carbon to remove theprotecting benzyi group. a' bis(2-chloroethyl)-lower alkylarnine or abis(2- chloroethyi N-lhydroxytiower)-alkyl]amine. to give thecorresponding desired .compound of fonnuia l wherein Y is anamino(lower)alkyl in which the amino d. Preparation and Conversion ofintermediates of Formula X (Y' I Mid-L).

intermediates of formula X in which Y is Alk*L wherein Aiit and L are asdefined in the first instance. -areobtaincdwhen a starting material offormula ii is condensed. witha 5-, .or 6-halioketone of formulaR'CO-AlitF-L in which R'.Aik and L are as defined in the first instance.in the presence of a suitableacid catalyst according to the conditionsdescribed above for to its oxime which on reduction with a complexmetal." The haiokctones are'either known. for example. 4.

hydride yields the corresponding primary amine of for defined in thefirst instance and Ya '-jAlk -NR"Rlin which Alk is CH, or.Alk-CH,wherein Alk is as de fined in the first instance and R" and R', arehydrogen. I

6s gart. i962. pp. Sill-i076.

if desired the lattercompounds of formula lmay be further N-aikyiated onthe nitrogen of the primary amine with theappropriate lower'alkyi halideto the chlorobuttih-Zone. or they may be prepared by known mula l inwhich R. R. R. R. R. R". R and X are as" 'metht ids. forinstance. secfRodds Chemistry of Car- 5 bon Compounds. cited above.-=.Vol. lc. pp.-7l and Thercaftersthcse intermediates of formulaX are treated withtwomolar equivalents or more of anamine corresponding compounds of formulalinwhich Y is of formulaHNRR" in which R" and R" are as defined in thefirst instance to yield the compounds of formula I in which R. R". R".R. R". R. R and X are asdescribed in the first instance and Y is-Alk-NR"R in which Alk is Aik as defined in the first instance and R" tand R are as defined in the first instance. Preferred conditions forthis reaction include the use of a suitable inert solvent. for example.tetrahydrofuran. temperatures ranging from 40-l0()C. or at the boilingpoint of the reaction mixture and a reaction time of from eight to 24hours.

e. Preparation and Conversion of intermediates of Formula X (YAikNR*"COR") intermediates of formula X in which Y is AlkNR" "COR"wherein Alk. R and R are as defined in the first instance are readilyobtained by the condensation (ll lX X) by using ketoamides of forrnuiain which R'Alk. R and R' are as defined in thefirst instance togetherwith the appropriate starting material of formula II. f

The ketoamides used herein are either known. for example.formamidoacetone [see A. Treibs and W. Sutter. Chem. Ber.. 84. 96 (195i)and R. H. Wiley and O.

H. Borum. J. Amer. Chem. Soc.. 70.2005 (1948)] or may be preparedbyknown procedures. for example. see Methoden der Organischen Chemie.cited above. Vol. Xl/l. i957. especially pp. 58 62. 285- 289 and 508509. and F. F. Blicke. Organic Reactions. l. 303

Thereafter. reduction with a complex metal hydride. described in section(a). converts the instant intermediates of formula lX to compounds offormula I in which instance and Y is AlkNR"R" in which Alk and Ri is hy4O drogen or-lower alkyl and R? is lower alkyl.

f. Preparation and Conversion of intermediates of Formula X (Y Alk NO.)

intermediates of fonnula [X in which Y is Alk-NO, wherein Alk is asdefined in the first instance. are obtained by the condensation (ll IXX) when the starting materials of formula ii and appropriate a-. /3-.

yand o-nitroitetones of formula R'j-Alk-NO.

in which R and Alk are as defined in the first instance are employedtherein in the presence of a suitable acid.-

Thereafter. these intermediates of formula X are r duced with a complexmetal hydride. preferably lithiu aluminum hydride. to afford thecompounds of fornai l in which R. R. R". R. R. R. R and X are as defimin in the first instance and Z is -AlkNR"R" in which A is as defined inthe first instance and R and R" are h drogen.

if desired the latter compounds are N-alkylated a cording to the methodsdescribed in section (0) to gi the compounds of formula I in which R. R.R". R. R R". R and X are as defined in the first instance and isAlk-NRR" in which Allt is as defined in the first i stance. R" ishydrogen or lower alkyl and R" is lower a ltyi.

g. Preparation of Compounds of Formula X (Y m AlkNR'R) Cbmpound ofFormula 1 (Y AikNR'R) The above described starting materials of formulain which R. R. R. R. R. R and X are as defined the first instance arecondensed in the presence of 1 acid catalyst with an aminoketone offormula RC( Aik-NR' R" in which R. Alk. R and R are as defint in thefirst instance to give directly the indenopyra andindenothiopyranalkylamine derivatives of formu l of this invention Therequisite aminokctones for this reaction are t ther known. for example.l-dimethylaminobutanone. l-methylamino-3-pentanone. see F. Biiekc. citedabove. or they may be prepared by knov procedures. for example. seeMethoden der Organ Chemie. cited above. Vol. Xl/l. i957. pp. 58 o 285289 and $08 509. v

in practising this present condensation it is general advantageous toutilize substantially equimol amounts of the starting material offormula ll or lla a: the amino ketone in the presence of an acidcatalyst. this particular condensation the amount of the aft mentionedacid catalyst to employ ranges genera from about l.0l to I00 molarequivalentswith res-pt to the amount of aminoketonc reactant. a rangefrom l.05 to l0 molar equivalents being preferred. C tionaily. one mayemploy the acid addition salts of t aformentioned aminoketones. forexample the hydt chloride or the sulfate salt. in this case the amountacid catalyst may range from 0.0l to I00 molar cqui\ ients. preferably0.l to lo molar equivalents. Boron t fluoride is a preferred acidcatalyst for the present ctdensation. The reaction may be performed comniently and advantagcouslywithout a solvent. aithou a high boilingsolvent. for example toluene. O-Xylcne isobutyl ether. may used.Reaction time and tcnlpt ature depe'nds on the particular reactantsemploy and may varied. The most convenient reaction tir is fromone-halfto '48 hours. preferably one-half to fo hours. and reactiontemperatures from 20 to I00 preferably 40 to 80C. The reaction in eachindividt case is performed preferably at the lowest temperatu at whichthe reaction proceeds smoothly and ex el tioasly with a minimum ofdecomposition.

in the case where the starting material is one of it mula il in which Xis S-SO..-Na or S--SO..-

. it is preferable to have at least one equivalent of wai present in thereaction mixture. T his water may added directly to the reaction or itmay be included part ofthe acid catalyst. Examples of the latter instanwould be when p-toluencsulfonic acid containing Wtii of crystallizationor concentrated hydrochloric acid employed as 'the acid catalyst.

With reference to the preparation of the indenopyranandindenothiopyranalkylamine derivatives of forv mulu la. the replacementof the starting material of formula II in any of the aforementionedprocesses (a) to (g) with the starting material of formula Ila.

II n

in which R. R. R. R. R. R and X is as defined in the first instance.gives the corresponding intermediate of formula Xu.

the steps described hereinbefore for effecting the correspondingtransformation of intermediates of formula X to the compounds of formulaI.

In other words the treatment of the starting material of formula Ilawith a compound of formula in which R and Y are as defined in the firstinstance according to the conditions of the condensation (II IX'X).described hereinbefore. gives the correspondthesis. 4i. 53 (l96l) toobtain the corresponding 2- indanone. Treatment of the latter compoundwith the appropriate Reformatski reagent of formula ZCRRCOOR" in which 2is bromine or chlorine. R" is lower alkyl and R and R" are as describedin the first instance. followed by dehydration with phosphorousoxychioride of the lower alkyl ester of the resulting2-hydroxyindane-2-acetie acid derivative gives the corresponding loweralkyl ester of the indene-Z-acetic acid derivative. Hydrolysis of thelatter derivative with sodium'or potassium hydroxide gives thecorresponding indene-2-acetic acid derivative. Reduction of the latterwith lithium aluminum hydride yields the desired starting material offormula Ila.

Alternatively. the starting material of formula Ila in which X ishydroxy. R and R are hydrogen and R.

R. R and R are as defined in the first instance is obtained by treatingthe appropriately substituted indanone of formula IV with about onemolar equivalent of butyllithium. followed by treatment with theappropriate reagent of formula ZCRCRCOOR. described above. to obtain thecorresponding lower alkyl ester of the l-oxoindane-2-acetic acidderivative. Reduction of the latter derivative with lithium aluminumhydride followed by dehydration with sullfuric acid in ethanol of theresulting l-hydroxyindane-2-ethanol derivative gives the desiredstarting material of formula Ila (R and R" H). v

The requisite starting material of formula Ila in which X is hydroxyland R'*.R". R. R. R and R are as defined in the first instance isavailable also by general synthesis involving the treatment of anappropriately substituted indanone of formula IV with about a molarequivalent of butyllithium inan inert solvent, preferably etherrfollowedby treatment with the appropriate ethylene oxide derivative of formulaVIII to obtain the corresponding Z-(hydroxyethyl)-l-indanone. derivaingintermediate "of fonnuia' Xa. the latter compound I being thecorresponding indenopyranor indenothiopyranalkylamine of fonnula Ia oran intermediate therefor.

The requisite starting material of formula Ila in whichgen is obtainedreadily by reduction of indene-Z-aeetie N tive. Reduction of the latterderivative with lithium aluminum hydride followed by dehydration withsulfuric acid in ethanol of the resulting l-hydroxyindane-2- ethanolderivative as described previously gives the desired starting materialsof formula Ila.

The requisite starting material of formula Ila in which X is mercapto.SSO;.Na or SSO,.-K is obtained from the corresponding starting materialof formula Ila in which X is hydroxy inthe same manner as 'describedabove for transforming the starting material of formula II in which X ishydroxyl to the corresponding starting material of formula II in which Xis mereapto. SSO,,'Na'and --SSO --K.

{The following examples illustrate further this invent On.

EXAMPLE I 3 -(2-Bromoethyl)-indene l'l g) is subjected to refiux for 3hr. with a solution of l3.3 g of sodium thiosulfate in I00 ml of waterand 2001 ml of ethanol. The solvents are remo'ved'under reduced pressureto give the corresponding sodium indeneethyl thiosulfate derivative (II:R. R. R. R. R and R H and X S-SO..-Na).' The latter compound isdissolved in a solutlonof NaOH l5 g) in ml of water. Ethanol (300 mlisadded) The solution is heated to reflux for 2 hr.. allowed to cool. andextracted with three portions benzene-hexane (l:3) to yieldbis-[w-(B-indenyUethyll-disulfide. nmr (CDCl.,): 6 3.02 (.r. 8H). 3.33(m.

4H). 6.25 (m. 2H). 7.30 (m. 8H). as an oil. The latter compound 12 g) inanhydrous ether is added dropwise with efficient stirring to asuspension of lithium aluminum hydride (2.5 g) in ether (200ml). Thereaction mixture is stirred at room temp. overnight. decomposed with 10ml of water. and the precipitate collected on a filter. The filtratcisdried (M380 Evaporation of the solution gives the title compound. nmr(CDCi 8 L48 (l. lH). 2.83 (m. 4H). 3.32 (m. 2H). 6.25 (m. 1H). 7.30 (m.4H).

By following the procedure of this example other starting materials offormula 11 (X -SH or S--SO.,Na. for example those described in Examples56 to l06 are prepared by the appropriate choice of the appropriatelysubstituted 3-(2-bromoethyl) l-Methyll.3.4.9-tetrahydroindeno[2,l-c]-pyranl I. acetic acid (X;'R CH R. R". R.R". R and R H. X O and Y CH COOH) To a solution of indene-B-ethanol (8g) and methyl acetoacetate (6 g) in 250 ml of dry benzene containinghydrated alkali-aluminum silicate (Molecular Sieves etherate and themixture stirred at room temperature for 4 hr. An additional 1 ml ofboron trifluoridectheratc is added. the reaction mixture is stirred atambient temperature overnight and then heated at reflux for 1 hr. Thehydrated alkali-aluminum silicate-is collected and the filtrate washedwith l0% solution of sodium bicarbonate and water. After drying overmagnesium'sulfate the benzene is removed under reduced pressureaffording indeno[ 2.l-clpyranl-acetlc acid methyl ester. v,..., 1724 cm.

Hydrolysis of. this ester to the title compound is effected as follows:The latter ester (1 1.5 g) is dissolved l-methyi-l .3.4.9-tetrahydr oin400 ml of methanoland the solution mixed with a so lution of l2 3 ofsodium hydroxide in lOO ml of water.

The resultingmixture is keptat room temperature overnight. Methanol 'isremoved by evaporation. The 1 residue. is diluted with water. Theaqueous solution is extracted repeatedly with ether, and acidified with6N hydrochloric acid. The resulting precipitate is extracted with ether.The ether extract is dried (MgSO,). filtered and concentrated. Theresidue is crystallized:

compound. m.p. 97 --99C. IM-" the ample. in this case. l-methyll 3.4.9-tetrahydroindeno[2.l-c]pyran-l-acetic acid ethyl ester is obtained asthe ester.

An equivalent amount of propyl acetoacetate may replace methylacetoacetate in the procedure of this example. in this case. l-methyil.349- tetrahydroindeno[ 2. l -c]pyranl -acetic acid propyl ester-isobtained as the ester.

EXAMPLE 3 l-Methyl'l .3.4.9-tetrahydroindeno[ 2. l -c]pyranl propionicacid (X; R I CH R". R. R. R". R and R H. X O and Y CH,CH,COOH) A mixtureof indene-B-ethanol (l5 8). dry benzene (300 ml). levulinic acid (22.6g). boron trifluoride etherate (3 ml) and hydrated alkali-aluminumsilicate (Molecular Sieves No. 4) is stirred at ambient temperature for2 hr.

The reaction mixture is filtered. The filtrate is washed three timeswith 5N NaOH; the combined aqueous phase is washed twice with ether andthen rendered acidic with cold diluted HCl. The aqueous phase isextracted with chloroform. The chloroform extract is dried (M1 andevaporated to dryness. The residue is crystallized from ether-hexane toafford the title I700, nmr (CDCL 8 L4 (s. 3H). 2.12 (m. 4H). 2.5 (m.2H), 3.25 (r. 2H).

EXAMPLE 4 l-Methyll .3.4.9-tetrahydroindeno[2. l -c lthiopyranlaceticacid (X; R CH3. R". R. R. R. R and R H. X S and Y CH,COOH) Amixture of indene-Zi-ethanethiol (8.0 g). methyl acetoacetate (6 g) andp-toluenesulfonic acid (0.8 g) in benzene (200 ml) is heated at refluxusing a water separator for 5 hr. After cooling. the reaction mixture iswashed with 10% solution of sodium bicarbonate and water. The benzene isremoved under reduced pressure. The residue is the corresponding methylester of title compound. l-methyll .3.4.9- tetrahydroindenolZ. l -cl-thiopyranl -acetic acid methyl ester. v,...,,""',, i730 cm".

The latter ester is dissolved in 200 ml of methanol and the I00 mi ofl.25 N NaOH is added. After stirring under reflux for 3 hr.. themethanol is removed by evaporation and the aqueous residue extractedwith ether. Theaqueous-layer is then rendered acidic with 6N HCl andextracted with ether. The ether extract is dried (MgSO.).-filteredandevaporated to dryness. The residue is crystallized from ether to afiordthe title compound. m.p. li9 l2lC. v,,.,,,"""",, 3000. i700 cm.'.

procedure of Examples or 4 are followed to prepare. other compounds offormula X in which R. R".

R. R. R. a". R and x are as defined in the first instanceand Y is COQR"or Alk'-COOR" wherein R" and AIR! are as defined in the first'instance.Examples of such compounds of formula X are listed in Tables I t and II.in each of these examples are equivalent amount of thestartingmaterialof formula ll listed therein is used instead of the startingmaterial of formula II descrlbed' in the procedures of Examples 2 and 4.Note that in each of these examples the ester obtained prior tohydrolysis is a corresponding ester compound of formula X.

Similarly, the procedure of Example 3 may he used formula ll. listedtherein. to prepare the products listed in Tables I and II. In this casean equivalent amount of the starting material of is used instead of thestarting mziteriai of formula II described in Example 3 together with anequivalent amount of the requisite kctoucid.

TABLE I PRODUCT: (PREFIX LISTED BELOWl-IJA STARTING MATERIAL KETOESTEROF 9-tetmhydroindeno- 0F FORMULA II FORMULA IZI-eIpyran-I- EX. IN WHICHX IS OH R Alk'-COCR"' (SUFFIX LISTED BELOW) Rf R" R R" R" R Mid-CO R'"PREFIX/[SUFFIX 5 H H H H H H CH, (O (,H, I-mcthyl/lcarboxylle acid m.l4I-l43'C h (H H H H H G (0 (,H IcthyI-.-mcth ll/ cartxixylic uci 7I--C,H, H H H 5-CH: CH i--C H, CO CH, I..'i-diimpmp I-b.9-

diiincthylllcar nryllc ac d 8 CH, CH H H $--0H H CH, CO CH b-hydru xy- I.Jj-trimethyi/Icarhoxylic acid 9 H H H 7-C,H, C H, n-(XM, CO CHiI.9-dIcthyI-lropyll/ cnri'xixylic ac d in H I-C,H, H H I-C, H, n-C.H..CO CH I-huIyI-4.9-diimpmpyI/Icarbuxylic acid II CH, CH (,H, CH, H C,Hn-C.H,. CO CH, l-butyi-4.4.9-

tricthyl-J.li'dimcthylll carhuxylic acid I2 H l H CH H H H CH cmco C,Hlfladimcthyillacctic ac: l3 H H H H H H (,H, (H- CO (,H, I-cthyI/laccticacid 14 H H H H H H n-C H CH,OO H, l-pmpy'Il/acetic acid,

mp. Ill IBJ'C l 5 H H H H H l-C H CH,CO C- H I -lmprupyi/lucetic acid IIt CH H H H H n--C H CH CO C H .i-mcthyl- I -pmpyI/I acetic acid i 7 CH3H (1H3 H H CH3 C3"; C-H5 i.4-dicthyl-3.9-

dimethyll/acctie acid It H H H CH I CH, CH(CH,)CO (,H, a-LQ-triimcthyI/Iacetic acid I 9 H H H H (,H n---C' H, C( CHmCO (,H I-butyI-9-cthyla,a-dimcthylll acetic acid :0 H H H H H H t-QH, CHfiO (,H,I-t-butyI/lacetlc acid 2| H H H H H H n-C H CHflO C,H I-bltyI/l'aceticaci 22 H H H H 7--CH C,H, n-C,H,. CH,CO C,HJ 9-cthyl-ti-methyilpropyI/lacctic acid 2.1 H H H H -Br (RH, (,H, CH O (1H,6-bmm0-L9-diethyil/ acetic acid 24 H H H H i-CH H CH, (H.CO CH,I.6-dImcthyi/l acetic acid 25 H H H H 5- t- I CH, CH CO C H6-acctoxy-9-t-butyl- OCOCH, (3H,: l-methyillaeetic' :0 H H H H I 5- I-CH5 1- cH,co C,H 6-bcnzyInxy-9- hcnzyl- (,H IwpmpyI-l-methyl/l my aceticacid 2 7 H H H 4--CH, CH; n-C H, CH CO (.H $.9-dlmcethyi- I- l royll/acctic acid 2K H H H 6-CH. H n-C,H (Hm (3H,, thyIl-l-propyI/l aceticacid 29 H H H 5- NO, n- I n-C H capo H, I .9-dlpropyl- C l-I,flmtrollucetlc we 30 H H CH, CH. H CH, n-C H, CH CO cm,4.4.9-trimcthyl-i- H pmpylllacctic acid 3i CH H H 5 -OC H, H CI"; I C Hncthoxy-a.a. l-

trifJhyV/muc t t w ac 32 CH, CH GIN C,H b-QH; n-CKH; n-QH, CIRLMibi-IWLGJIJJ v tetramcthyI-4,4.7- I q i tricthyIl/acetlc acid 33 CH, Hn-C,,H, n--C H, 4-1: H CH, (5H,, CH(CH,)CO C H, lethyl-a.3.9-trinnthylmmii-tripropyillncctie M .\-I II H H H H H n-CM, C(CHNI QO (.I-l.mfimofiyl-I-propyI/I ac I C H C H, 4-C H, C H, t(. H C(I-C,,H ).CO (,H,i-t-butyl-or.a- 5 (,HA Ci a a a u t I I i a i i 1 dimpmpyldlafifis t i Ii hexaethyl/lacetic acid 36 H H H H 4--I .r CH5 I-C,.H CH,CH,CO C H9-methyli-5-Iodo-l- ImpropyIl/lpmpinnic acid I TABLE I -CominuedVPRODUC'T: (PREFIX LISTED BELOW)- 1 TABLE II -Cntinued STAR'flNGMATERIAL OF FORMULA ll IN WHICH X' IS SH R' R R KETOESTER OF FORMULAR'j-AllU-CO-OR" PRODUCT: (PREFIX LISTED BELOW)-l.3.4,9-tetruhydroindeno- [2.l-clthlopyran-l- (SUFFIX LISTED BELOW Mid-CO R"'PREFIX/[SUFFIX (M N H H H CH 94 H H CH, CH; H H

97 (,H, H H H S-NO, CH

99 CH, CH, H H H CH an H H H H H H 102 cH H H H H cm 10.1 cm. H H Ho-No, H

I H H H H 7-OH n-CJi cat.

ti-nltro-fl-propylll pmpionic acid l-butyl-a.a.{3.B.hertumethyl/lproplonlc a: ti

,9-diethyi-B.fl.4,4- tetrumethyll/propionic acid l.9-dimethyl-5-propkmoxy l-propyl. aJLB-triethyi/l pro lonic acid aJI-dimcthyil ,3-dlpropyl-S-mcthoxyl/ propionic acidl.9-dimethyl-6-nitroflfifij-pentaethyll/ propionic acidB.1-dipropyl-3.3.5.9-

u aiz i CH... CH: CO

I a a i z n C: H: CO

tetraethyl/lpropionlc acid 7.7-dlethyll-propyl- 3,3 ,9-trimethyi/lbutyric acid l -butyl-7-ethoxyaBS-triethyl/l propionic acidl-methyll/butyric acid l-ethyl-yJS-trimethyll/butyric acidl-butyl-Ii-ethyI-7- nitro-a.fi.7-trimethyl// butyric acidafi-diethyi-BJ-dimethyll.$.9-tripropylll hutyric ucld 9-butyl- I-ethyl-8- hydroxy-magysytetramethyl/Ibutyric acid9-t-butyl-$-ethoxylethyl-a.a.fl.fi;y,7.3 .4- octamethyll/butyric acld i3 ia CIHB EXAMPLE 107 the residue partitioned between chloroform andwater The chloroform layer is washed with water, drier (M580 andconcentrated to afiord the title com pound as an oil. v,,,,, I625. I400,1075 cm". nm (CDC'a) 6 1.55 (.s'. 3H). 3.07 2.53 (m, 2H), 2.74 (.i 2H),2.92 and 3.07(.\'. 6H), 3.42 (m, 2H), 3.96 (r, 2H) 7.25 (m. 4H).

In the same manner but replacing the 40% aqueou solution ofdimethylamine with an equivalent amoun of the amines of formula HNR"R.ammonium hydrox ide (concentrated). methylamine (40% aqueous solu tion).n-hcxylamine aqueous solution), diethyl amine aqueous solution),isopropylamine (409 aqueous solution ethylamine aqueous solution) NO. OFTHE PRODUCT: ((PREFIX LISTED BELOW)- EXAMPLE IN WHICHI.3.4.9-TETRAHYDROINDENO[2.I-cl- STARTING MATERIAL IS PYRAN-l-(SUFFIXLISTED BELOW" EX. PREPARED AMINE PREFIX/ISUFFIX lilo 27 piperidincl-i($.9-dimethyi-l-propyil/ acetyl lpipcridine I II? .il morphoiine 4-la.a.-triethyi- 3.3-dimethyl-oarthoxyllacetyiI- morphnline I 88 37pipcrnzlnc l-l t tlaicetoxyl .9 diethyl-a.3.3-

4.4-pentamcthyl/lpropionyl lpiperazlne I 89 4t) N-plperazincl-i 2-h\slroxycthyl I-Hl l-hutylethanol man/3.3.4.6.9-heptamcthylll pmpionyllpipcrazine I 90 4i pyrrolidine l-lt l.3.9-trimethyl-e.a.-dipropylllpmplonyllpgrrolidlne I9l 43 morphoiine 4-lll.9-dict yl-ABAA-tetramcthyll/pmpionyl lmorphollne I92 48 N-pmp ll-propyl-4-|(l-butyl-Wcthoxyplpcrav. ne 11.13.94riethylI/propionyl pl razlne I93 49pyrrolldlne l-Wl methyl/[butyryl lpyrrolldine I 94 49 N-piperuzincl-(hydrnxymethyl i-4-ll I -methyll/ methanol hutyryl lplperazine I95 51pipcridinc l-| y.-y-d ethyll-pmpyl-JJM- trimclhyl/Ibutyryl 1p peridineEXAMPLE I96 25 dimethyl- I .3.4.9-tetrahydroindeno[ 2. I -c ]thiopyran-I N.N. I -Trimethyi- I .3.4.9-tetrahydroindeno[ 2. I -cthiopyrani-acctamide IX. R CH... R. R". R. R". R" and R' H. X S and Y'CH- COMCH M I-Methyi- I .3.4.9-tetrahydroindeno[2. l -c]thiopyran- 3wise to the solution and the resultant mixture stirred at 35 -C. for 90min. Dimethyiaminc (60 ml of a 40% aqueous solution) is added andstirring continued at room temperature for 30 min. The solvent isremoved under reduced pressure. The remaining suspension is distributedbetween chloroform and water. The organic phase is separated. washedwith water. dried (MgSO and concentrated to give the title compound as asolid. nmr (CDCI 6 L75 (s, 3H). 2.95 (broad m. IZH). 3.50 (I. 2H), 7.26(m. 4H).

In the same manner but replacing the 400i aqueous solution oidimethyiamine with an equivalent amount oi the amines of formula HNRR".ammonium hydroxide (concentrated), methyiamine (40% aqueous solution).n-hexylamine aqueous solution). diethylamine aqueous solution).isopropylamine aqueous solution), ethylamine aqueous solution).pyrrolidine (50% aqueous solution). piperidine. morphoiine.N-methylpiperazine. l -methyl 1 {3.4.9- tetrahydroindeno[ 2. l-c]thiopyranl -acetamide. N. i

ucetamide. N hexyi- I -methyi- I .3 .4.9- tetrahydroindenol 2. i-c]thiopyran- I -acetamide. N.N- diethyl- I -methyl-I.3.4.9-tetrahydroindeno[ 2. l clthiopyranl-acetamide. I-methyl-N-isopropyll .3.4.9-tetrahydroindeno[ 2. l -c ]thiopyranlacetamide. N-ethyll -methyl- I 3.49- tetrahydroindeno[ 2, I-c]thiopyranl -acetamide i-[( lmethyi-l .3.4.9-tetrahydroindeno[ 2, l-c]thiopyran- I yl )acetyl ]-pyrrolidine. l-[( l-methyll ,3,4.9-tetrahydroindenoi 2. I -c]thiopyran- I -yl )acetyi piperidine. 4-[(l-methyl- I 3.49- tetrahydroindenoi 2. I -c ]thiopyranl -yl )acetyimorphoiine. and l-methyl-4-[( l-methyl- I .3.4.9- tetrahydroindeno[ 2, l-c ]thiopyran- I -yl )-acetyi ]pipera- 40 zine. are obtained.respectively.

1 By following the procedure of Example I96 but using as startingmaterial an equivalent amount of one of the acid compounds of formula X(X S) descrihed in Examples 56 to I06. instead oi l-methyl- I .3.4.9-

4.1tetrahytlroindenol2.l-clthlopyran-I-acetie acid. and

using an equivalent amount of an appropriate amine such as ammonia or aprimary or secondary amine described in Example I96. then thecorresponding amide compound of'formula X (X S) is obtained.

Examples of such amides are listed as products in Tables V and Vitogether with the appropriate starting material of formula II (X S) andamine used for the preparation of the amide. in each case the startingma- TABLE V NO. OF THE PRODUCT: [(PREFIX LISTED BELOW)-I..'i.-

EXAMPLE IN WHICH 4.9-TETRAHYDROlNDENOi2J-cITHIO STARTING MATERIAL ISPYRAN-i-(SUFFIX LISTED BELOW-H EX.

EX. AMINE PREFIX/ISUF- FIX I97 ll? (ll Nli N.l -tiimalhyl/IpropinnamitieI9Il iil NH. i-methyl/Iproplumrmide I99 87 (CHMNH N.N.l-trimethyiilproionamide. 200 R7 (C HmNH N.N-diethy l- I -methy l/propionnmide 20] $6ICH I NH N.N.l -trimeth 'lI/carboxumide.

runr (CDCI L68 (s.3H). 2.65(m.2H)..1.|2(s.6H).3.54 im.2H). 4.08 (m.2H).2H). 7.28 (mAH)

1. A COMPOUND SELECTED FROM THOSE OF FORMULA 2.N,1-Dimethyl-1,3,4,9-tetrahydroindeno(2,1-c)-pyran-1-ethylamine. 3.N,N,1-Trimethyl-1,3,4,5-tetrahydroindeno(1,2-c)-pyran-1-ethylamine, asclaimed in claim
 1. 4.N,N,1-Trimethyl-1,3,4,5-tetrahydroindeno(1,2-c)-pyran-1-ethylaminehydrochloride, as claimed in claim
 1. 5.N,N,1-Trimethyl-1,3,4,5-tetrahydroindeno(1,2-c)-thiopyran-1-ethylamine,as claimed in claim
 1. 6. A process for preparing a compound of formulaI or Ia
 7. The process of claim 6 in which the acid catalyst is selectedfrom the group consisting of p-toluenesulfonic acid, aluminum chloride,phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloricacid, perchloric acid, trifluoroacetic acid, sulfuric acid, andpolyphosphoric acid.
 8. The process of claim 6 in which the compound offormula I or Ia is reacted with a pharmaceutically acceptable acid togive the corresponding acid addition salt.
 9. The process of claim 6,for preparing a compound of formula I, in which R1 is methyl, R2 to R7inclusive are hydrogen, X is oxy, Y is CH2CH2N(CH3)2, X1 is hydroxy andY1 is CH2COOH or CH2COOCH3.
 10. The process of claim 6, for preparing acompound of formula I, in which R1 is methyl, R2 to R7 inclusive arehydrogen X is oxy, Y is CH2CH2CH2N(CH3)2, X1 is hydroxy, Y1 isCH2CH2COOH or CH2CH2COOCH3.
 11. The process of claim 6, for preparing acompound of formula I, in which R1 is methyl, R2 to R7 inclusive arehydrogen X is oxy, Y is CH2N(CH3)2, X1 is hydroxy and Y1 is COOH orCOOC2H5.
 12. The process of claim 6, for preparing a compound of formulaI, in which R1 is methyl, R2 to R7 inclusive are hydrogen, X is thio, Yis CH2CH2N(CH3)2, X1 is mercapto and Y1 is CH2COOH or CH2COOCH3.
 13. Theprocess of claim 6, for preparing a compound of formula I, in which R1is methyl, R2 to R7 inclusive are hydrogen, X is oxy, Y is CH2CH2NHCH3,X1 is hydroxy and Y1 is CH2COOH or CH2COOCH3.
 14. The process of claim6, for preparing a compound of formula Ia , in which R1 is methyl, R2 toR7 inclusive are hydrogen, X is oxy, Y is CH2CH2N(CH3), X1 is hydroxyand Y1 is CH2COOH or CH2COOCH3.
 15. A process for preparing a compoundof formula I or Ia
 16. The process of claim 15 in which the acidcatalyst is selected from the group consisting of p-toluenesulfonicacid, aluminum chloride, phosphorus pentoxide, boron trifluOride, zincchloride, hydrochloric acid, perchloric acid, trifluoroacetic acid,sulfuric acid, and polyphosphoric acid.
 17. The process of claim 15 inwhich the compound of formula 1 or 1a is reacted with a pharmaceuticallyacceptable acid to give the corresponding acid addition salt.
 18. Theprocess of claim 15, for preparing a compound of formula 1, in which R1is methyl, R2 to R7 inclusive are hydrogen, X is oxy, Y is CH2N(CH3)2,X1 is hydroxy and Y1 is CON(CH3)2.
 19. A process for preparing acompound of formula 1 or 1a
 20. The process of claim 19 in which theacid catalyst is selected from the group consisting of p-toluenesulfonicacid, aluminum chloride, phosphorus pentoxide, boron trifluoride, zincchloride, hydrochloric acid, perchloric acid, trifluoroacetic acid,sulfuric acid, and polyphosphoric acid.
 21. The process of claim 19 inwhich the compound of formula I or Ia is reacted with a pharmaceuticallyacceptable acid to give the corresponding acid addition salt.
 22. Theprocess of claim 19, for preparing a compound of formula I, in which R1is methyl, R2 to R7 inclusive are hydrogen, X is oxy, Y is CH2N(CH3)2,X1 is hydroxy and Y1 is CH2OCOCH3.
 23. A process for preparing acompound of formula I or Ia
 24. The process of claim 23 in which theacid catalyst is selected from the group consisting of p-toluenesulfonicacid, aluminum chloride, phosphorus pentoxide, boron trifluoride, ziNcchloride, hydrochloric acid, perchloric acid, trifluoroacetic acid,sulfuric acid, and polyphosphoric acid.
 25. The process of claim 23 inwhich the compound of formula I or Ia is reacted with a pharmaceuticallyacceptable acid to give the corresponding acid addition salt.
 26. Theprocess of claim 23, for preparing a compound of formula I, in which R1is methyl, R2 to R7 inclusive are hydrogen, X is oxy, Y is CH2N(CH3)2,X1 is hydroxy and Y1 is CH2OCOCH3.
 27. A process for preparing acompound of formula I or Ia
 28. A process of claim 27 in which the acidcatalyst is selected from the group consisting of p-toluenesulfonicacid, aluminum chloride, phosphorus pentoxide, boron trifluoride, zincchloride, hydrochloric acid, perchloric acid, trifluoroacetic acid,sulfuric acid, and polyphosphoric acid.
 29. The process of claim 27 inwich the compound of formulae I or Ia is reacted with a pharmaceuticallyacceptable acid to gIve the corresponding acid addition salt.
 30. Theprocess of claim 27, for preparing a compound of formula I, in which R1is methyl, R2 to R7 inclusion are hydrogen, X is oxy, Y is CH2N(CH3)2,X1 is hydroxy and Y1 is CH2OCOCH3.
 31. A process for preparing acompound of formula I or Ia
 32. The process of claim 31 in which theacid catalyst is selected from the group consisting of p-toluenesulfonicacid, aluminum chloride, phosphorus pentoxide, boron trifluoride, zincchloride, hydrochloric acid, perchloric acid, trifluoroacetic acid,sulfuric acid, and polyphosphoric acid.
 33. The process of claim 31 inwhich the compound of formula I or Ia is reacted with a pharmaceuticallyacceptable acid to give the corresponding acid addition salt.
 34. Theprocess of claim 31 in which the primary amine is further reacted with alower alkyl halide to obtain the corresponding compound of formulae I orIa in which R8 is hydrogen or lower alkyl and R9 is lower alkyl.
 35. Theprocess of claim 31, for preparing a compound of formula I, in which R1is methyl, R2 to R7 inclusive are hydrogen, X is oxy, Y is CH2NH2, X1 ishydroxy and Y1 is CH2OCOCH3.
 36. A process for preparing a compound offormulae I or Ia
 37. The process of claim 36 in which the acid catalystis selected from the group consisting of p-toluenesulfonic acid,aluminum chloride, phosphorus pentoxide, boron trifluoride, zincchloride, hydrochloric acid, perchloric acid, trifluoroacetic acid,sulfouric acid, and polyphosphoric acid.
 38. The process of claim 36 inwhich the compound of formula I or Ia is reacted with a pharmaceuticallyacceptable acid to give the corresponding acid addition salt.
 39. Theprocess of claim 36, for preparing a compound of formula I, in which R1is methyl, R2 to R7 inclusive are hydrogen, X is oxy, Y is CH2N(CH3)2,X1 is hydroxy and Y1 is CH2l.
 40. A process for preparing a compound offormulae I or Ia
 41. The process of claim 40 in which the acid catalystis selected from the group consisting of p-toluenesulfonic acid,aluminum chloride, phosphorus pentoxide, boron trifluoride, zincchloride, hydrochloric acid, perchloric acid, trifluoroacetic acid,sulfuric acid, and polyphosphoric acid.
 42. The process of claim 40 inwhich the compound of formulae I or Ia is reacted with apharmaceutically acceptable acid to give the corresponding acid additionsalt.
 43. The process of claim 40, for preparing a compound of formulaI, in which R1 is methyl, R2 to R7 inclusive are hydrogen, X is oxy, Yis CH2CH2NH(C2H5), X1 is hydroxy and Y1 is CH2CH2NHCOCH3.
 44. A processfor preparing a compound of formula I or Ia
 45. The process of claim 44in which the acid catalyst is selected from the group consisting ofp-toluenesulfonic acid, aluminum chloride, phosphorus pentoxide, borontrifluoride, zinc chloride, hydrochloric acid, perchloric acid,trifluoracetic acid, sulfuric acid, and polyphosphoric acid.
 46. Theprocess of claim 44 in which the compound of formulae I or Ia is reactedwith a pharmaceutically acceptable acid to give the corresponding acidaddition salt.
 47. The process of claim 44 in which the primary amine isfurther reacted with a lower alkyl halide to obtain the correspondingcompound of formulae I or Ia in which R8 is hydrogen or lower alkyl andR9 is lower alkyl.
 48. The process of claim 44, for preparing a compoundof formula I, in which R1 is methyl, R2 to R7 inclusive are hydrogen, Xis oxy, Y is CH2CH2CH2NH2, X1 is hydroxy, and Y1 is CH2CH2CH2NO2.